Amino propyl tetrahydro-1,4-oxazines

ABSTRACT

IN WHICH R IS LOWER ALKYL HAVING UP TO 5 CARBON ATOMS, PHENYL OR METHYLPHENYL, A IS OXIZATION, AND R1 IS NITROPHENYL, NITROXYPHENYL, OR TRIMETHOXYPHENYL; OR ITS PHYSIOLOGICALLY ACCEPTABLE ACID SALTS. THE AMIDES ARE USEFUL FOR TREATING CARDIAC ACID DISTRUBANCES SUCH AS MYOCARIDIAL ANOXIA, CORONARY INSUFFICIENCY, MYOCARDIAL INFARCTION, AND ARRHYTHMIA.   R-O-CH2-CH(-CH2-A)-NH-CO-R1   AN AMINE OF THE FORMULA

United States Patent 3,806,505 AMINO PROPYL TETRAHYDRO-lA-OXAZINES Mauvernay Roland-Yves, Riom, Busch Norbert, Loubeyrat, Simond Jacques, Chamalieres, and Moleyre Jacques, Mozac, France, assignors to Centre Europeen de Recherches Mauvemay C.E.R.M.

No Drawing. Original application July 16, 1969, Ser. No. 842,388, now Patent No. 3,663,566. Divided and this application Dec. 29, 1970, Ser. No. 102,526 Claims priority, application66France, July 17, 1968,

159,4 Int. Cl. C07d 87/42 US. Cl. 260-2472 A 8 Claims coronary insufiiciency, myocardial infarction, and arrhythmia.

This application is a division of copending application Ser. No. 842,388, filed July 16, 1969 and now issued as US. Pat. 3,663,566. This application claims the priority as perfected in the parent of the application filed in France on July 17, 1968.

This invention is concerned with certain novel amides, with a process for their preparation and with compositions containing them.

We have found that amides of the formula:

NH-O 0-R1 (I) in which R is an alkyl, alkenyl, alkynyl, aryl or arylalkyl radical, all of which may be unsubstituted or substituted, A is a tertiary amine group included in a heterocyclic group, and R is an aromatic radical which may, if desired, be substituted in the nucleus, or an arylalkyl radical, and their addition salts with physiologically acceptable acids, have valuable cardic-vascular properties, and are suitable for therapeutic use.

The amides of Formula I and their acid addition salts are novel and constitute one aspect of the present invention.

The amides of Formula I can be prepared by a four stage process.

Stage 1: Conversion of an alcohol of the formula: ROCH CHOHCH A, into the corresponding chloride by reaction with thionyl chloride in chloroform.

Stage 2: Treatment of the resulting chloro derivative with potassium phthalimide in dimethylformamide.

Stage 3: Conversion of the resulting phthalimide into an amine of the formula,

-O-CH CHNH -CH -A by treatment with hydrazine in accordance with the process described by Ing and Manske (J. Chem. Soc., London, 1926: 2348).

Stage 4: Reaction of the resulting amine with an acid chloride of the formula, CICOR wherein R is as defined above to obtain the desired final product.

The use of this process to prepare the compound in which R is CH: -CH2CH/ A is L and R is OCH:

O CH:

CHI

that is to say the compound 1-[3-isoamyloxy-2-(3,4,5-trimethoxy)benzoylamino'] propyl tetrahydro-1,4-oxazine will now be described by way of example only.

EXAMPLE First stage.l-(3-isoamyloxy-2-chloro)-propyltetrahydro-1,4oxazine A solution of 180 g. of $001 in anhydrous CHCl was added to a solution of 231 g. (1 M) of the aminoalcohol in 400 ml. of anhydrous CHCl with thorough stirring and while limiting the rise in temperature to not more than 55 C.

After completion of the addition, the whole was refluxed for 4 hours and, after evaporation of the solvent, the residue was poured onto crushed ice and rendered alkaline by the addition of 33% aqueous NaOH. The product was extracted with ether and, after drying of the extract over anhydrous Na SO and distillation of the solvent, it was distilled under vacuum to give 175 g. of a colorless liquid, B.P. C; n =1.4625.

Second and third stages.l-(3-isoamyloxy-2-amino)- propyl-tetrahydro-1,4-oxazine Fourth stage-1 [3-isoarnyloxy 2 (3,4,5-trimethxy)- b o hloride arn'no r0 1 tetrah dr 1 4- (CH3)2CH-CH;-CH:OCHr-CH-CHq-N 1:;- yl c 1 1 P W y o I lne NH: q

0 (CH) (DH-(CH) O-CH CH-CHl-N II 5 3 2 I 2 l l O NH: NH

CHaO

0 CH;0 0001 M02115); ll 0 5 CH: 175 g. (0.7 M) of the halogen derivative obtained 1n Stage 1, 132 g. (0.8 M) of potassium phthalimide, and 300 ml. of dimethylformamide were heated together for (CHMCH CH2 CH2 0 CH 00H, 8 hours at 110 C. After cooling, the KCl precipitate was filtered oil and washed with 100 ml. of dimethylform- NH-OO OCH; amide. The solvent was evacuated under vacuum and the residue, which did not crystallize was used in its crude CH; state in the next stage.

500 ml. of ethanol at 95 C. and 39 g. of hydrazine MCZHOBHCI hydrate were added to the residue and the whole was refluxed for 2 hours. The mixture was acidified with con- 23 g. (0.1 M) of 3,4,5-trimethoxyrbenzoyl chloride were centrated HCl. The phthalhydrazine precipitate was added, with thorough stirring and at a temperature of 0 filtered 011 and washed with alcohol. The filtrate was 0., to a solution of 22.9 g. (0.1 M) of the previously concentrated to 100 ml. 500 ml. of water were added and, 25 prepared diamine in 100 ml. of chloroform. After the after filtration, this was concentrated to 200 ml. It was addition, the mixture was allowed to return to ambient rendered alkaline with NaOH and the oil formed temperature and then left to stand overnight. was extracted with ether. Distillation under vacuum gave The solvent was removed, the residue was taken up 95 g. of product, B.P. (3 mm. Hg) 127-131 G. in ether, filtered and washed with water. This ether solu- The product was then purified by crystallizing its di- 30 tion was dried over Na SO filtered and the product was fumarate from absolute alcohol and then recrystallizing crystallized by cooling. from the same solvent. Recryslallization from anhydrous ether gave 30 g. of After liberation of the base, the product was distilled a crystalline product, M.P. 63-64 C. N calculated again under vacuum and 63 g. of a chromatographically =6.60%. N found=6.57%. Yield=%. pure product were obtained, B.P. (3 mm. Hg) 129 C. 35 The fumarate of this base was also prepared. Table I n =1.4650. shows the characteristics of this compound and of a Total yield of the two stages from the halogen derivanumber of other compounds of Formula I and their salts tive=39%. that have been prepared in an exactly analogous manner.

0 N ai R A R1 Constants 1 CEaOH CH \N CHaO Base, M.W. 410, m.p. 87 C Fumarate, M.W. 526, m.p. 117 C.

P CH O CH:

CHM!) 2 OE; Same as above.. Same as above Base, M.W. 424, m.p. 63-64" C... Fumarate, M.W. 540, m.p. 128 C.

/CH2CHzCH2-' CHa 3; Q CH do do Base, M.W. 444, m.p. C Fumarate, M.W. 560, m.p. C;

4 Same as above .-do O N G Base, M.W. 398, m.p. 70 C Fumarate, M.W. 514, m.p. C.

5 Q .....do Same as above.....'..-... Base, N.W. 385, m.p. 135 0..... H01, M.W. 421.5, m.p. C.

6 Same as above .-do CHaO Base, MW. 432, m.p. 95 C H01, M.W. 468.5, m.p. 111 C.

CHaA

7 dn (in Q Base, M.W. 341, m.p. 70 0 Dl-HCI, 414, m.p. 140 C.

8 do \N CHsO Base, M.W. 414, nonerystalllne... H01, M.W. 450.5, m.p. C.

CHaO

CHJ)

9 --do Base, N.W. 369, noncrystalline.. H01, M.W. 405.5, m.p. 140 0.

Same as above-.

As indicated above, the compounds of Formula I and their salts have valuable pharmacodynamic properties.

First, their acute toxicity, evaluated by detemining the LD according to the conventional method of Behrens and Karber (Arch. f. exp. pharm., 177, 379 (1935)) is substantially the same as those of drugs known at the present time for the same purposes. Thus, the LD in mg./kg., in the mouse when given orally, is as follows for some of the above-mentioned compounds and some known The LD evaluated by the same method, but given intravenously, is 44 mg./kg. for Compound No. 8, while for Lidocaine, Ajmaline and Propanol, it is 32, 26 and 30 mg./kg. respectively.

Results (average of a batch of five dogs) Com- Coro- Venpound Dose, nary Fre- Arterial trieular N o. mg./kg. rate quency pressure gauge pO:

1 5 132.4 112.6 15.5 $5.9 126.6 2 5 T38.6 t4.9 16.5 6.6 129 3 5 T 13 T 3 l 9 T 10 T4 4 5 T20 113.5 113 T2 T26 These compounds as a whole have valuable antiarrhythmic properties, causing the disappearance of the extra systoles induced by a strong dose of adrenaline injected intravenously and reducing the excitability of the'isolated auricle.

Compound No. 8 is remarkable in this respecst, showing an anti-arrhythmic activity that is greatly superior in all respects to that of drugs already known for this purpose.

The various aspects of these activities have been compared and the results are set out below, the index 100 being taken arbitrarily as a reference activity for each type of test for Compound No. 8.

l) Arrhythmia caused by coronary ligature in a waking dog (Harris method) Each value is the average of the results obtained from 10 animals.

A. INTRAVENOUS ADMINISTRATION 5 mgJkg.

Compound Ajma- Hydro- Lido- Procain- Pheny- Propra- Products No. 8 line quinidine caine amide toine nolol Activity (Ex. 8, index 100) 100 40 95 15 20 65 Duration of action (min.) 1017" 8'40" 2 8'07" 2 :0 17'15" B. ORAL ADMINISTRATION, mgJkg.

Compound ydroqui- Products No. 8 Ajmaline nidine Propranolol Lidocaine Activity (Ex. 8, index 100) 100 100 71 43 0 because of destruction Start of action 36 min 53 min 44 min 5 hrs. min.. Maximum duration of action Morfiir than 6 hrs. 30 min Mp1;r than Norm-z activity insufliciently characteristic for its duration to be indicated.

Second, these compounds act generally on the coronary rate, arterial tension, the forces of the cardiac contractions and the coronary oxygen pressure, p0 these eiiects having been demonstrated for a number of the compounds using the following method of investigation.

The thorax of the test animal, a dog, was opened under chloralosis by resection of the fifth rib on the right side. A strain gauge was sewn onto the right ventricle. A catheter of the largest possible diameter was introduced into the coronary sinus through an opening in the right auricle and fixed by a ligature placed very near the auricle.

The coronary venous blood flowed into a rotameter placed in a thermostatically controlled vessel and then, in the same vessel, was brought into contact with an oxygen macroelectrode (Beckrnan). It returned to the right jugular by a duct penetrated by a fine catheter, which conveyed blood to a Technicon autoanalyzer in which the total carbon dioxide and ammonia were determined continuously. The contraction of the myocardium, the D electrocardiogram, the integrated coronary rate, the arterial pressure and the p0 were recorded on a Beckman dynograph. I

The products were administered venously (external saphenous vein) with as low injection taking 1 minute.

(2) Arrhythmia caused by strong doses of ouabain in an anaesthetized dog.

(Intravenous injection of ,ug. of ouabain in 1 minute causes very severe arrhythmia 15 to 25 minutes afterwards.)

INTRAVENOUS ADMINISTRATION, 1.25 rug/kg. [Average of results from 10 animals] Compound Lido Proeain- Products N o. 8 caine amide Activity (Ex. 8, index 100 100 10 Duration 0! action (min.) 22 8 INTRAVENOUS ADMINISTRATION, 2.5 mgJkg.

active than Compound No. 8, but the duration of action Percent of anaesthesia at 2% concentration During the first 30 mins.

During the 24th Products hr.

Compound No. 8 Lidocaine The activity of Compound No. 8 according to the concentration is comparable to that of Lidocaine, but its duration of action is much greater.

Activity as visceral analgesic (method of Koster in the mouse-oral administration) Products: ED in mg./ kg.

Compound No. 8 170. Lidocaine Without action.

The compounds of Formula I therefore appear to be suitable for the following therapeutic indications:

Myocardial anoxia Coronary insufliciency, angina Myocardial infarction Cardiac insufiiciency linked with disturbances of coronary circulation Disturbances of rhythm Compound 8 is particularly advantageous for the latter indication.

These compounds may be administered orally, in the form of tablets, gelules, capsules, soluble granulates, drops or syrup; rectally, in the form of suppositories or rectal capsules, or by injection, in the form of bottles of lyophilized powder or ampoules. For this purpose the com- Mode of administra- Unit dose, Preferred tron mg. dose, mg.

What we claim is: 1. An amide of the formula:

NH-O 0-R1 in which R is lower alkyl having up to 5 carbon atoms, phenyl or methylphenyl, A is oxazino, and R is nitrm phenyl, nitroxyphenyl, or trimethoxyphenyl; or physiologically acceptable acid salts of the amide.

2. 1-[3-isobutyloxy 2 (3,4,5 trimethoxy)-benzoylamino]-propyl-tetrahydro-1,4-oxazine.

3. 1-[3-isoamyloxy 2 (3,4,5 trimethoxy)-benzoyl amino]-propyl-tetrahydro-1,4-oxazine.

4. 1-[3-benzyloxy 2 (3,4,5 trimethoxy) benzoylamino] -propyl-tetrahydro-1,4-oxazine.

5. 1-[3-benzyloxy 2 (4-nitro)-benzylamino]-propyltetrahydro-l,4-oxazine.

6. 1-[3-phenoxy 2 (4-nitro)-benzoylamino1-propyltetrahydro-1,4-oxazine.

7. 1-[3-phenoxy 2 (3,4,5-trimethoxy)-benzylamino]- propyl-tetrahydro-1,4-oxazine.

8. 1-(3-phenoxy 2 nicotinoylamino)-propyl-tetrahydro-1,4-oxazine.

References Cited UNITED STATES PATENTS 3,723,416 3/1973 Thominet 260-239 BF HENRY R. IILES, Primary Examiner G. T. TODD, Assistant Examiner US. Cl. X.R. 260-295.5 A 

